PROJECT SUMMARY A bioengineered, three-dimensional (3-D), human tissue model that recapitulates complex structures and functional units of living, human organs provides an attractive, animal model alternative platform to study human disease and accelerate drug development. Recent 3-D biofabrication progress has made it possible to replicate a 3-D human skin consisting of both the epidermis of differentiated stratums for external protection and the dermis containing collagen and fibroblasts for elasticity and mechanical strength. We have advanced this full-thickness skin equivalent by establishing a vascularized, immune competent skin-on-chip microfluidic platform to model viral-host interactions in human herpes simplex virus (HSV) infection, a disease affecting two-thirds of the human population with increasing worldwide prevalence and medical relevance. This human, skin-on-chip system closely mimics the natural skin architecture and is capable of drug perfusion and immune-cell infiltration, providing a practical in vitro system for modeling of HSV infection in humans and for antiviral drug screening and preclinical evaluation. We propose two specific aims in this application: 1) High-throughput screening to identify potential antiviral compounds for blocking HSV infection using fabricated 3-D skin model; 2) Validating candidate antivirals in vascularized 3-D skin models fabricated with patient-specific primary keratinocyte, fibroblast and endothelium cells from a cohort of diverse HSV outcomes. The proposed research will be conducted in a close partnership with the 3-D Bioprinting Laboratory at the National Center for Advancing Translational Sciences (NCATS). The collaboration will leverage the resources and capabilities of the NCATS program aiming to greatly advance the process of discovery and development of new medicines and improve prediction of the effectiveness and toxicity of novel therapeutics in treating humans. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page